Toxicology Research最新文献

Synthetic cathinones (SCs), a group of new psychoactive substances (NPS), are designer molecules with hallucinogenic and psychostimulatory effects. Although the structural similarities of SCs to amphetamines suggest that they may have similar toxicity profiles to those of amphetamine congeners, little is known about SCs from a toxicological point of view. In the present study, the toxicity profiles of commonly encountered SCs (n = 65), listed in the 2020 Report of the United Nations Office on Drugs and Crime (UNODC), were evaluated using in silico methods. We aimed to gain a deeper understanding of key toxicological endpoints: acute oral toxicity (LD₅₀), mutagenicity, genotoxicity, and carcinogenicity prediction using EPA TEST (v.5.1.2 and 4.2.1), VEGA (v.1.2.3), and ProTox (v.3.0). Physicochemical and pharmacokinetic (ADME) properties were estimated using SwissADME and pkCSM. 2,3-MDMC (41) was predicted to be the most lethal SC by the VEGA KNN and the EPA TEST v.5.1.2 with an oral rat LD₅₀ value of 105.17 and 117.77 mg/kg, respectively. 4-BEC (2) was the only molecule with a consensus score of positive prediction greater than 0.90 in both TEST mutagenicity models. 2,3-MDMC (41) and methylone (52) were predicted as carcinogenic by VEGA carcinogenicity CAESAR, ISS, IRFMN-ISSCAN-CGX, oral classification, and ProTox models. These two SCs were predicted to be active by VEGA chromosomal aberration (CORAL) and in vitro micronuclei-inducing activity (IRFMN-VERMEER) models. Our results concluded that given the prolonged exposure duration and age range, the genotoxic and carcinogenic potential of SCs should be considered, among other known toxic effects.

Since the Industrial Revolution, ecological damage, ecosystem disruption, and climate change acceleration have frequently resulted from human advancement at the price of the environment. Due to the rise in illnesses, Industry 6.0 calls for a renewed dedication to sustainability with latest technologies. Focused research and creative solutions are needed to achieve the UN Sustainable Development Goals (SDGs), especially 3, 9, 13, 14, 15, 17. A promising sustainable technology for enhancing healthcare while reducing environmental effect is Metal Organic Frameworks (MOFs). MOFs are perfect for drug administration because of their high surface areas, adjustable pore sizes, and remarkable drug-loading capacities. They are created by combining advanced artificial intelligence, intelligent manufacturing, and quantum computing. Researchers can create MOFs with functional groups or ligands that bind selectively to target cells or tissues, minimizing off-target effects, thanks to the distinct benefits that families like MIL, HKUST, UiO, and ZIF etc. offer for targeted drug delivery. Combining MOFs with other nanomaterials results in multipurpose systems that can handle challenging biomedical issues. Despite its promise, there are still issues with MOFs' possible toxicity and long-term stability in physiological settings. To advance their medicinal applications, these problems must be resolved. Researchers can increase the usefulness of MOFs in medicine by critically analysing these limitations and putting up creative alternatives. The creation of MOFs especially with advanced technologies (additive manufacturing etc.) for drug delivery is a prime example of how scientific advancement and environmental stewardship may coexist to provide healthcare solutions that are advantageous to both people and the environment.

The latest studies have demonstrated that aberrant expression of microRNA-146a is related to cognitive decline. The rs57095329 polymorphism occurring in the miR-146a promoter modulates its expression and causes downstream pathogenicity. A case-control study in a Chinese Han population was established to investigate the genetic association between the miR-146a rs57095329 polymorphism and postoperative cognitive dysfunction (POCD). 242 patients with POCD and another 238 non-POCD cases were enrolled in the case-control study. Serum miR-146a levels were detected by qRT-PCR. miR-146a rs57095329 polymorphism was genotyped using the ABI PRISM SNaPshot method. The genetic association between the rs57095329 polymorphism and POCD was assessed by regression analysis. No significant difference was detected for age, gender and BMI between POCD and non-POCD groups. MiR-146a rs57095329 polymorphism revealed significant generic associations with POCD in both dominant and recessive models, and the AA genotype may increase the risk of developing POCD. qRT-PCR indicated the upregulation of miR-146a level in POCD group. Serum levels of miR-146a and inflammatory factors were higher in rs57095329 AA genotype carriers than in AG/GG genotype carriers. Rs57095329 polymorphism was independently associated with the development of POCD. In conclusion, miR-146a rs57095329 polymorphism was associated with POCD in the Chinese Han population. The rs57095329 AA genotype was the causative genotype for POCD and was related to the upregulation of miR-146a and inflammatory factor levels.

Background: Microplastics are tiny plastic particles, typically less than 5 mm in size, formed from the breakdown of larger plastic products. This breakdown releases additives, including benzyl butyl phthalate (BBP), into the environment. Humans can be exposed to BBP through contaminated food and water, inhalation, and dermal contact.

Aim: Research suggests that BBP, like other phthalates, may have neurotoxic effects, potentially contributing to neurodevelopmental disorders, though its specific toxic targets are not yet clear.

Methodology: In this study, high-performance computational methods were used to identify potential neurotoxic targets of BBP. The findings indicate that BBP has a strong potential to interact with Parkin (PRKN) and Pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1), with binding scores of -5.35 kcal/mol, -5.56 kcal/mol, respectively. The PRKN and PDK1 BBP complexes were stable throughout the simulation period, as evidenced by the system's backbone exhibiting slight fluctuations and binding energies confirmed by molecular dynamics (MD) simulation trajectories.

Results: The MMPBSA analysis revealed free binding energies of -21.29 kcal/mol and - 27.06 kcal/mol for the PRKN and PDK1 BBP complexes, respectively. The interaction energies of BBP with PRKN and PDK1 were also within an acceptable range, at -113.68 ± 3.1 kJ/mol and - 117.54 ± 6.2 kJ/mol, respectively. Additionally, density-functional theory (DFT) based optimization showed negative values for the highest occupied molecular orbital (HOMO) -6.934 eV and lowest unoccupied molecular orbital (LUMO) -1.562 eV, indicating that BBP is energetically stable, which is crucial for forming a stable ligand-protein complex.

Conclusion: Overall, the computational investigation reveals that BBP has the potential to interact with PRKN and PDK1, leading to neurodegeneration.

Objective: Organophosphorus Nerve Agent, VX [(O-Ethyl S-diisopropylaminomethyl) methylphosphonothioate] compound interferes with acetylcholine signaling by targeting the AChE enzyme. Studies suggest that in nerve agents poisoning, non-cholinergic effects are also responsible for damage in peripheral tissues including long term damage in brain. Present study reports cholinergic and non-cholinergic effects of VX poisoning and their prevention by use of N-acetylcysteine (NAC) in addition to conventional antidotes atropine sulphate and 2-PAM chloride as an antioxidant. NAC was chosen being an approved drug for medical conditions including oxidative damage and as mucolytic.

Results: Results of the study showed that after 1x LD ₅₀ exposure to VX and standard atropine and oxime therapy resulted in recovery of cholinesterase activity up to 51%, while additional NAC administration resulted in increased recovery up to 89% in brain cholinesterase activity. NAC also helped in maintaining intracellular and tissue GSH level, reduced ROS generation and lipid peroxidation. NAC treatment could able to reduce the lipid peroxidation (MDA) levels in liver of NAC administered groups as compared to standard treatment of atropine sulphate and PAM chloride at 10 LD ₅₀ VX. Likewise, a 20% higher level of GSH was found in NAC treated group at 1x LD ₅₀ dose in brain. Cell cycle analysis and histopathological results showed that NAC prevents VX induced damage.

Conclusion: it was found that use of antioxidant agent NAC along with standard atropine-oxime treatment is helpful in reducing the cholinergic and oxidative stress mediated toxicity induced by VX.

This study aims to assess the safety, efficacy, and mechanisms of Juanbilijieqing Fang in a mouse model of gouty arthritis. C57BL/6 mice were allocated into six groups: control, gouty arthritis model, and treatment groups receiving varying doses of Juanbilijieqing Fang (low, medium, high), along with a positive control group treated with febuxostat. Gouty arthritis was induced via MSU crystal injection following a high-fat diet. Mice were treated with Juanbilijieqing Fang or febuxostat, and safety was evaluated by measuring spleen, kidney, and liver indices. Efficacy was assessed by monitoring foot thickness, pain threshold, and biochemical markers, including serum uric acid (UA), myeloperoxidase (MPO), xanthine oxidase (XOD), and adenosine deaminase (ADA). Serum pro-inflammatory cytokines were analyzed, and intestinal inflammation and barrier integrity were examined through histological and molecular assays. Juanbilijieqing Fang did not significantly affect spleen, kidney, or liver indices, indicating its safety. Therapeutically, it significantly reduced foot swelling, improved pain threshold, and decreased serum uric acid levels. It also lowered MPO activity in foot tissue and reduced XOD and ADA activity in the liver. Additionally, the formula downregulated pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ, demonstrating a strong anti-inflammatory effect. It ameliorated gut inflammation by decreasing NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1) and enhanced gut mucosal integrity by upregulating ZO-1 and Occludin expression. Juanbilijieqing Fang is a safe and effective treatment for gouty arthritis, primarily through reducing systemic and intestinal inflammation and restoring gut barrier function.

This study explores the role of Argonaute 2 (AGO2) in the induction of apoptosis by arsenic in 16HBE cells and investigates the association between AGO2 expression and arsenic exposure in a human population. By silencing AGO2 with siRNA, we examined its impact on cell viability and apoptosis using CCK-8, HO-PI, and JC-1 assays, complemented by qRT-PCR and Western blot analyses for gene and protein expressions. Our findings revealed a significant correlation between AGO2 expression and levels of exposure to inorganic arsenic (iAs), which was more pronounced than with other arsenic forms such as monomethylarsonic (MMA) and dimethylarsinic acids (DMA). The results showed that silencing AGO2 not only reduced cell viability but also intensified apoptosis, highlighting its role in activating the p53 pathway. This was further supported by increased phosphorylation of p53 at Ser392 and Thr55, reinforcing AGO2's involvement in apoptotic processes. The study underscores the potential of AGO2 as a therapeutic target in arsenic-related pathologies and highlights the critical need for managing occupational exposure to arsenic.

Ovarian cancer (OC) is a significant cause of cancer-related mortality among women. This study explores the efficacy of Achillea millefolium L. (A. millefolium) extract, known for its phytoestrogenic properties, in treating OC through hormonal and metabolic modulation. Using a Wistar rat model, OC was induced with 7,12-dimethylbenz(a)anthracene (DMBA), and the effects of A. millefolium, both alone and in combination with paclitaxel (PTX), were evaluated. The study involved five groups of ten rats each: normal, OC, and those receiving 100 mg/kg of A. millefolium with or without PTX. Key hormonal levels, oxidative stress markers, and inflammatory cytokines were measured. Additionally, ovarian tissues were analyzed for malondialdehyde and ferric reducing ability of plasma, while gene and protein expressions related to apoptosis were assessed. Results showed that A. millefolium, particularly when combined with PTX, reduced the luteinizing hormone/follicle-stimulating hormone ratio, increased antioxidant enzyme activity, and upregulated apoptosis-related pathways, leading to higher p53 expression and fewer Ki-67 positive cells. These findings suggest A. millefolium's potential as a complementary therapy for women with OC, particularly those with ovulation disorders.

The incidence of acute organophosphate (OP) poisoning has steadily increased in developing countries. Many studies showed that oxidative stress could have a significant role in its mechanism. The current study aimed to evaluate the role of N acetylcysteine (NAC) as an antioxidant in acute OP poisoned. A randomized, controlled, parallel-group trial was conducted in the period from the beginning of January 2022 to the end of June 2022. The study included 56 acute OP poisoned patients admitted to the intensive care unit (ICU) at the Poison Control Center of Ain Shams University Hospitals within 6 h after the exposure. The patients were randomly allocated in two equal groups; group (A): received the standard treatment plus NAC in a total dose of 300 mg/kg administered intravenously (IV) while group (B) received the standard treatment. Then both groups were compared as regards clinical parameters, laboratory investigations, ECG, and outcomes. Baseline parameters were comparable between the groups. However, NAC treatment significantly elevated concentrations of both serum catalase and glutathione peroxidase levels at 24 h, it did not significantly affect the total dose of atropine required, duration of atropine and oximes treatment or need for mechanical ventilation, and length of hospital stay. Mortality was lower in the NAC group (2 out of 28) than the standard treatment-only group (5 out of 28) but the difference was not statistically significant. This trial found that NAC improved antioxidant enzyme levels including serum CAT and GPX but did not affect clinically relevant outcomes.

Aluminium phosphide poison become an alarming, well-known, effective suicidal poison with a high mortality rate. There is a need for a simple tool that can triage patients with bad prognosis. The study aimed to assess the accuracy of ejection fraction as a predictor of mortality and morbidity in acute aluminium phosphide toxicity cases. The study involved 70 cases of acutely aluminium phosphide-poisoned patients in our hospital from January 2021 to January 2024. The study found that 54.3% of the cases were males and 45.7% were females, with a mean age of 22.4 ± 11.8 years old. The oral route was the route of administration of all cases, and the intention of poisoning was intentional in 84.3% of cases. Regarding the outcome of patients, 62.9% of the cases recovered, and 37.1% died. The Receiver Operating Characteristic Curve found that the ejection fraction below 37.5% had an accuracy rate of 96.8% with excellent discrimination for mortality, sensitivity of 100%, specificity of 93.2%, positive predictive value of 89.6%, and negative predictive value of 100%. The ejection fraction below 52.5% had an accuracy rate of 89% with good discrimination for complications, sensitivity of 83.3%, specificity of 96.8%, positive predictive value of 90.9%, and negative predictive value of 93.7%. So, the ejection fraction plays an essential tool in predicting mortality and complications in acute aluminium phosphide toxicity and should be assessed on every patient in the first 24 h of admission to facilitate the triage of these patients.